Antibody-drug conjugates (ADCs) are a new type of targeted therapy consisting of three components: a target-specific antibody (e.g., a monoclonal antibody, mAb) or antibody fragment (e.g., a single-chain variable fragment (scFv)); a payload, often a cytotoxic drug; and a linker connecting the drug to the antibody. Upon administration, the antibody binds to a target cell and the drug exerts its therapeutic effect, for example, by optional cleavage from the ADC and/or by internalization in the cell or proximity to the outside of the cell. See, e.g., Ducry et al., Bioconjugate Chemistry (2010) 21: 5-13; Kovtun et al., Cancer Research (2006) 66: 3214-21; and Kovtun et al., Cancer Letters (2007) 255 (2): 232-40. Targeted therapies are envisioned to provide many advantages including, but not limited to, decreased side effects and a wider therapeutic window as compared to untargeted therapies.
The type of linker used is an important consideration in the design of the ADC. For example, ADCs with cleavable linkers are thought to have a less favorable therapeutic window, and are best designed for targets, such as tumor cell surface antigens that are internalized efficiently. Hydrophilic linkers, such as linkers which contain multiple polyethyleneglycol (PEG) units, are known to help prevent the drug being pumped out of resistant cancer cells through MDR (multiple drug resistance) transporters. See, e.g., P. Diamond, Genetic Engineering & Biotechnology News, “Antibody-Drug Conjugates Stage a Comeback” (Mar. 9, 2010). The linker should also be designed in a manner that ensures stability during circulation in blood but allows for the rapid release of the drug, preferably inside the target cell. Several types of enzymatically degradable and non-degradable linkers for ADCs have also been explored, such as cleavable acid- and peptidase-labile linkers and non-cleavable linkers such as thioethers. See, e.g., Ducry et al., Bioconjugate Chemistry (2010) 21: 5-13.